Is LDLR p.Cys95Ser (c.283T>A) pathogenic?

LDLR p.Cys95Ser (c.283T>A) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-07-22). AlphaMissense: likely pathogenic (0.9982); Very rare (popmax 8.48e-05%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Cys95Ser (c.283T>A)?

LDLR p.Cys95Ser (c.283T>A) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys95Ser (c.283T>A) in the general population?

LDLR p.Cys95Ser (c.283T>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Cys95Ser (c.283T>A)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

LDLR p.Cys95Ser

c.283T>A · rs879254456 · VCV251110

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic ✓ concordant with ClinVar · top 1% in LDLR
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -12.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,868 alleles

Overall 6.2e-05% 1/1,613,932 alleles · very rare exomes 1/1,461,624 · genomes 0/152,308 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LDLR
Protein: p.Cys95Ser
Coding: c.283T>A
MANE Select: NM_000527
dbSNP: rs879254456
Type: single nucleotide variant
Location: chr19:11102756 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 95: a β-strand; a disulfide bond; the ldl-receptor class a 2 domain; a UniProt-annotated variant site (in fhcl1)

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LDLR p.Cys95Gly Likely pathogenic ★★★ same residue
LDLR p.Cys95Tyr Likely pathogenic ★★★ same residue
LDLR p.Cys95Arg Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys95Phe Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys95Ter Pathogenic ★★ same residue
LDLR p.Cys95= Likely benign ★★ same residue
LDLR p.Cys95Trp Pathogenic/Likely pathogenic ★★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ldlr-p-cys95ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown